R-spondins are a recently characterized small family of growth factors. Here we show that human R-spondin1 (RSPO1) is the gene disrupted in a recessive syndrome characterized by XX sex reversal, palmoplantar hyperkeratosis and predisposition to squamous cell carcinoma of the skin. Our data show, for the first time, that disruption of a single gene can lead to complete female-to-male sex reversal in the absence of the testis-determining gene, SRY.

Our data demonstrate that: (i) cultured autografts bearing stem cells can indeed rapidly and permanently cover a large body surface; and (ii) fibrin is a suitable substrate for keratinocyte cultivation and transplantation. These data lend strength to the concept that the success of cell therapy at a clinical level requires cultivation and transplantation of stem cells. We therefore suggest that the proposal of a culture system aimed at the replacement of any severely damaged self-renewing tissue should be preceded by a careful evaluation of its stem cell population.

High-mobility group box 1 (HMGB1) protein is a multifunctional cytokine involved in inflammatory responses and tissue repair. In this study, it was examined whether HMGB1 plays a role in skin wound repair both in normoglycemic and diabetic mice. HMGB1 was detected in the nucleus of skin cells, and accumulated in the cytoplasm of epidermal cells in the wounded skin. Diabetic human and mouse skin showed more reduced HMGB1 levels than their normoglycemic counterparts. Topical application of HMGB1 to the wounds of diabetic mice enhanced arteriole density, granulation tissue deposition, and accelerated wound healing. In contrast, HMGB1 had no effect in normoglycemic mouse skin wounds, where endogenous HMGB1 levels may be adequate for optimal wound closure. Accordingly, inhibition of endogenous HMGB1 impaired wound healing in normal mice but had no effect in diabetic mice. Finally, HMGB1 had a chemotactic effect on skin fibroblasts and keratinoyctes in vitro. In conclusion, lower HMGB1 levels in diabetic skin may play an important role in impaired wound healing and this defect may be overcome by the topical application of HMGB1.

No abstract

Detailed information on QoL in patients with vitiligo may lead dermatologists to pay particular attention to patient categories at risk for a high QoL impairment.

Accumulation of senescent cells contributes to the reduced regenerative capacity in aged tissues. By evaluating the molecular pathways of senescence in relation to proliferative potential of primary keratinocyte cultures from young and old healthy donors, and from young patients with inherited defects leading to premature aging, we demonstrated that p16(INK4a) is a reliable marker of both physiological and premature epidermal aging. Analysis of the expression and activity of p16(INK4a) regulators showed that stem cell depletion, reduced proliferation, and p16(INK4a) upregulation in keratinocytes derived from the chronologically and prematurely aged epidermis strongly correlate with Bmi-1 downregulation. In highly proliferative tissues, replicative and premature senescence participate in determining senescent cell accumulation. Our findings demonstrated that Bmi-1 is downregulated in human keratinocytes during both in vitro processes, in parallel with p16(INK4a) upregulation and accomplishment of clonal conversion. When premature senescence was induced by specific exogenous stimuli, concomitant Ets-1 upregulation was also observed. Moreover, Bmi-1 inhibited Ets-1-mediated p16(INK4a) upregulation. Finally, Bmi-1 overexpression reduced p16(INK4a) promoter activity and decreased protein expression in aged and diseased keratinocytes, inducing a delay of clonal conversion and an increase of cell clonogenic ability. Altogether these findings underline a key role of Bmi-1 downregulation in enforcing aging in primary human keratinocytes.

Vitiligo is a multifactorial disorder characterized by the appearance of white maculae that may spread over the entire body skin. Depigmentation arises from the loss of functioning melanocytes. Non segmental vitiligo (NSV) is the most common form of the disease: it is usually progressive and may be associated with familiarity and autoimmunity. Segmental vitiligo (SV) frequently stabilizes few years after its onset. Vitiligo etiology involves multiple pathogenetic factors, most of them working in concert. Impaired antioxidative defences lead to accumulation of reactive oxygen species (ROS), which affect melanocytes. Mitochondrial membrane lipid peroxidation may participate to ROS overproduction. A temporal sequence may connect oxidative stress and autoimmunity. Overall, a genetic predisposition renders vitiligo melanocytes more susceptible to precipitating factors than normal healthy melanocytes. The definition of isolated or superimposed manifestations of polygenic skin disorders has been proposed for SV and SV-NSV association. Keratinocytes and melanocytes are both affected and apoptosis, ageing or melanocythorragy are the ultimate effects of the complex deregulation in vitiligo skin. Pathogenetic therapies mainly act by inducing immunosuppression and stimulation of melanocyte proliferation and migration. Here the most popular hypotheses for the pathogenesis of vitiligo are summarized. Fundamental cellular, biochemical and molecular alterations accounting for melanocyte destruction in vitiligo are also described. Last, pathogenetic approaches in the treatment of such a complex disease are discussed, with particular consideration on the cellular and molecular targets of the current therapies.

The term palmoplantar keratoderma (PPK) indicates any form of persistent thickening of the epidermis of palms and soles and includes genetic as well as acquired conditions. We review the nosology of hereditary PPKs that comprise an increasing number of entities with different prognoses, and a multitude of associated cutaneous and extracutaneous features. On the basis of the phenotypic consequences of the underlying genetic defect, hereditary PPKs may be divided into the following: (i) non-syndromic, isolated PPKs, which are characterized by a unique or predominant palmoplantar involvement; (ii) non-syndromic PPKs with additional distinctive cutaneous and adnexal manifestations, here named complex PPKs; (iii) syndromic PPKs, in which PPK is associated with specific extracutaneous manifestations. To date, the diagnosis of the different hereditary PPKs is based mainly on clinical history and features combined with histopathological findings. In recent years, the exponentially increasing use of next-generation sequencing technologies has led to the identification of several novel disease genes, and thus substantially contributed to elucidate the molecular basis of such a heterogeneous group of disorders. Here, we focus on hereditary non-syndromic isolated and complex PPKs. Syndromic PPKs are reviewed in the second part of this 2-part article, where other well-defined genetic diseases, which may present PPK among their phenotypic manifestations, are also listed and diagnostic and therapeutic approaches for PPKs are summarized.